1. Field of the Invention
The invention relates to a treatment of bacterial meningitis.
2. Description of the Related Art
Pathogens, including bacteria, viruses and fungi, are normally kept out of the body's central nervous system (CNS) by two unique anatomical features commonly referred to as the blood-brain barrier (BBB), FIGS. 1 and 2, and the blood-cerebrospinal fluid barrier (CSFB), FIG. 3. As a result bacterial infections are an infrequent occurrence, usually induced by severe systemic infections or trauma, but are serious and difficult to treat when they do occur.
The BBB and CSFB impede movement of most constituents of the blood into the brain (and cerebrospinal fluid) and are essential for the normal CNS function. In addition to serving as a barrier limiting access of pathogens (including viruses and fungi) they also limit access of cellular elements of the blood (lymphocytes, monocytes and neutrophils) and most antibodies and antibiotics from entering the CNS.
The barriers are present in all regions of the brain, except those involved in regulating the endocrine and autonomic nervous systems of the body. As a result of this barrier phenomenon, the composition of interstitial fluid in the brain and cerebrospinal fluid differs from other interstitial body fluids.
Existence of a barrier between the brain and the rest of the body was first suggested by Paul Ehrlich, a noted bacteriologist, in the late 1800's. He observed that some dyes would stain all organs of an animal's body except the brain, following an IV injection. Ehrlich attributed this observation to the possibility that tissue in the CNS simply did not pickup up the dyes. Edwin Goldmann, one of Ehrlich's students in 1913, injected dye directly into cerebrospinal fluid, and found that the brain was dyed, but the rest of the body was not. The observations of Ehrlich and Goldmann clearly demonstrated the existence of some sort of barrier between the tissues of the CNS and the rest of the body.
The BBB essentially comprises three cellular elements of the brain's microvasculature; endothelial cells, astrocyte end-feet, and pericytes (PCs). Endothelial cells of the BBB differ from peripheral endothelial cells in most of the rest of the body by the absence of fenestrations and the existence of tight junctions (TJ's) between adjacent endothelial cells. Ultrastructurally the TJ's appear as sites of apparent fusion involving the outer leaflets of plasma membranes of adjacent endothelial cells. The TJ's created by the fusion selectively excludes most blood-borne substances and cellular elements from entering the brain. Astrocyte end-feet tightly ensheath the vessel wall and appear to be critical for the induction and maintenance of the BBB, but probably do not have a barrier function per se. The astrocyte-endothelial cell interaction is probably related to a system of signaling pathways, although the mechanism of this signal transduction is not completely understood. Pericytes are cells of microvessels, including capillaries, venuoles and arterioles. They are thought to provide structural stability to the vessel wall. A study has suggested that pericytes may prevent apoptosis of endothelial cells associated with these pericytes. In addition the pericytes exhibit phagocytic activity and may be involved in neuroimmune functions.
The fundamental structure of the BBB is illustrated in FIGS. 1 and 2. FIG. 1 shows in cross section a brain capillary 2. The brain capillary 2 is lined with tightly joined endothelial cells 3. FIG. 2 shows an enlarged section of the brain capillary 2 of FIG. 1. The blood-brain barrier 10 comprises a wall of endothelial cells 3 that faces, on one side, blood 14 transported by the capillary, and, on the other side, the brain parenchyma 16 and the cerebrospinal fluid (CSF) 17. The CSF bathes the brain and the spinal cord of the CNS. A number of functions have been ascribed to the CSF. An important function is to cushion the brain within its solid vault. The brain and CSF have about the same specific gravity so the brain simply floats in the fluid helping protect it from injury. The volume of CSF can vary based on the volume of the brain that may occur with vasodilation or swelling of parenchymal cells. The CSF is absorbed through the arachnoidal villi and probably performs, in addition to its protective effect, a specialized lymphatic system for the brain. The avg. cerebrospinal fluid pressure is 130 mm water. Tight junctions 18 between adjacent endothelial cells 3 form the BBB.
The CSFB functions, together with the BBB, to control the internal environment of the brain. Most of the CSF is produced from arterial blood by the choroid plexus of the ventricles of the brain by a combined process of diffusion, pinocytosis, and active transfer. Smaller mounts of CSF are secreted by the ependymal cells lining the ventricles of the brain and the central spinal canal. Ependymal cells are low columnar or cuboidal epithelial cells lining the ventricles of the brain and the central canal of the spinal cord. In some regions these cells are ciliated resulting in movement of the CSF. In the ventricles of the brain the ependymal cells are part of the choroid plexus which is responsible for the secretion of most of the CSF.
The choroid plexus is a vascular tissue found in all cerebral ventricles. It is composed of tufts of endothelial cells covered by differentiated ependymal epithelium. Morphologically the structure of ependymal cells is similar to other secretory cells. Unlike the capillaries that form the blood-brain barrier, choroid plexus capillaries are fenestrated and have no tight junctions. This endothelium, therefore, does not form a barrier to the movement of constituents of the blood as occurs in the BBB. Instead, the CSFB is formed in part by TJ's between the ependymal cells in the choroid plexus and those lining the ventricles and spinal canal. Pulsation of the choroid plexus and the cilia of the ependymal cells creates movement of the CSF through the ventricles and the central canal of the spinal cord. The CSF is absorbed by the arachnoid villi into the venous circulation.
FIG. 3 shows a schematic representation of meninges surrounding the brain. The meninges, another part of the CSFB, comprise pia matter 20 adjacent the brain parenchyma 16 and the CSF 17, the arachnoid membrane 22, the dura matter 24, bone 26, periosteum 28, and skin 30. The arachnoid membrane 22 comprises endothelial cells with TJ's similar to those of the BBB and the ependymal cells described above, and it defines the barrier portion of the CSFB in the meninges. Located between the pia matter 20 and the arachnoid membrane 22 is the intrathecal space 32. An intracthecal space may also be found in other parts of the CNS such as the spinal cord. FIG. 4 shows a cross sectional view of a spinal cord 40. The spinal cord also has several layers including dura matter 42, arachnoid membrane 44, pia mater 46, and spinal nerves 48. Located between the pia matter 46 of the spinal cord 40 and the arachnoid membrane 44 is the intrathecal space 50 also known as the subarachnoid cavity. Cerebrospinal fluid (CSF) surrounds both the spinal cord and the brain and fills the spaces including the ventricles of the brain and the central canal of the spinal cord in them.
Bacterial meningitis is a condition in which the meninges (e.g., the dura mater 24, the arachnoid membrane 22 and/or the pia mater 20) lining the brain have become inflamed as a result of infection with bacteria. The meninges can also be infected by an extension of brain parenchyma infection. There are a number of bacterial infections that are known to infect a body's CNS. The most common organisms involved in bacterial meningitis include Neisseria meningitidis (or meningococcus), Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. Less common bacterial causes include Listeria monocytogenes, Staphylococcus, Escherichia coli and Enterococcus. If not properly treated, bacterial meningitis may cause blindness, deafness, learning disabilities, brain damage, and death.
Heretofore, no effective treatment has been found for bacterial meningitis, although the mainstay of current treatment for bacterial meningitis is heavy antibiotic therapy. The antibiotics must be administered systemically at high doses, due to their relative inability to cross the blood-brain barrier. The major obstacle to developing drugs for the CNS is the physiology and structure of the CNS itself. The BBB and the CSFB allow only certain substances through and keep other harmful compounds and pathogens out. For example, oxygen, water, carbon dioxide, and other small lipid-soluble materials easily cross the BBB. Glucose amino acids, vitamins, and nucleosides are transferred across by specific carrier proteins, and ions cross the barrier via ion channels and an active transport system. Transmission of the remaining normal elements of the blood does not occur under normal circumstances. However, not only does the BBB keep out harmful elements, it is also nearly impenetrable to many antibiotics.
It is known to effectively treat bacterial infections in animals using a Cephalosporin class drug commonly termed Naxcel (ceftiofur sodium). Ceftiofur sodium is ineffective when taken orally because it remains in the intestine and does not disseminate in the body. But to be effective against an infection in the CNS, it would have to be administered by injection in high doses in order to permeate the BBB if at all. However, high does of the Cephalosporin class of drugs are known to result in seizures, if present in the CNS. A treatment is needed which can efficiently provide effective antibiotics to the CNS to treat such afflictions as bacterial meningitis.